Tripedia

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Prescribing Information

Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) (DTaP) is a vaccine used to prevent diphtheria, tetanus (lockjaw), and pertussis (whooping cough). It is an immunization. Common side effects include mild fever, redness, pain, tenderness, or swelling where the shot was given, fussiness for 1-3 days after the shot, tiredness or poor appetite for 1-3 days after the shot, or vomiting for 1-3 days after the shot.

A 0.5 mL dose of Tripedia vaccine is given to infants and children 6 weeks to 7 years of age (prior to seventh birthday) as a five-dose series. The series consists of a primary immunization course of three doses administered at 2, 4, and 6 months of age, followed by two booster doses, recommended at 15 to 18 months of age, and at 4 to 6 years of age, respectively. Consult your doctor for the immunization schedule. Tripedia may interact with steroids, cancer chemotherapy or radiation, azathioprine, basiliximab, cyclosporine, etanercept, leflunomide, muromonab-CD3, mycophenolate mofetil, sirolimus, or tacrolimus. Tell your doctor all medications and supplements you use. Tripedia may be harmful to a fetus and should not be given to a pregnant woman. Consult your doctor before breastfeeding.

Our Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

SIDE EFFECTS

Over 3, 000 US and 12, 000 German infants received one or more doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine as part of the primaryimmunization series in clinical trials conducted by the sponsor and the National Institutes of Health (NIH). A subset of over 1, 000 German and US children were monitored for adverse events through a fourth successive dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine. A subset of 580 German children were monitored for adverse events through a fifth successive dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine.

Over 400 children who had received three doses of whole-cell pertussisDTP vaccine were assessed for adverse events following a booster dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine at 15 to 20 months of age.

In a double-blind, comparative US trial, 673 infants were randomized to receive either 3 doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine or AvPs whole-cell pertussis DTP vaccine (Table 2).2 Safety data are available for 672 infants, including 505 who received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine and 167 who received whole-cell pertussis DTP vaccine. Following all three doses, rates for all reported local reactions, fever > 101°F, irritability, drowsiness, and anorexia were significantly less in Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine recipients. Reaction rates generally peaked within the first 24 hours, and decreased substantially over the next two days.2,27,28

TABLE 22ADVERSE EVENTS OCCURRING WITHIN 72 HOURS FOLLOWING THE FIRST THREE DOSES OF TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE OR WHOLE-CELL PERTUSSIS DTP VACCINE GIVEN TO INFANTS 2 TO 6 MONTHS OF AGE

* p < 0.01 when compared to whole-cell pertussis DTP vaccine for all doses. ** p < 0.05 when compared to whole-cell pertussis DTP vaccine. † For certain adverse events information was not available for a small number of infants.

Adverse event data for Tables 2-9 were actively collected using patient diaries, phone call follow-up, and/or by questioning the parent(s) at clinic visits. All data were recorded on standardized case report forms.

A similar reduction in adverse events was seen in a randomized, double-blind, comparative trial conducted in the US by the NIH when Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine was compared to Lederle Laboratories whole-cell pertussis DTP vaccine (Table 3).29 Each data point presented in Table 3 is a summary of the frequency of reactions following any of the three primary immunizing doses. Local adverse reactions, which include pain, erythema, swelling, and systemic reactions such as fever, anorexia, vomiting, drowsiness and fussiness may have occurred following any of the three primary vaccinations.

TABLE 329PERCENT OF INFANTS WHO WERE REPORTED TO HAVE HAD THE INDICATED REACTION BY THE THIRD EVENING AFTER ANY OF THE FIRST THREE DOSES OF TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE OR WHOLE-CELL PERTUSSIS DTP VACCINE

N¶

ERYTHEMA

SWELLING

PAIN†

FEVER* >101°F

ANOREXIA

VOMITING

DROWSINESS

FUSSINESS‡

Tripedia

Vaccine

135

32.6**

20.0**

9.6**

5.2**

22.2**

7.4

41.5**

19.3**

Whole-Cell

Pertussis

DTP Vaccine

371

72.7

60.9

40.2

15.9

35.0

13.7

62.0

41.5

* Rectal Temperatures **p < 0.01 when compared to whole-cell pertussis DTP vaccine. † Moderate or severe = cried or protested to touch or when leg moved. ‡ Moderate or severe = prolonged or persistent crying that could not be comforted and refusal to play. ¶N = Number of Infants

In a multicenter trial conducted by the NIH in the US, the frequency of adverse reactions following each dose in children who received only Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine is shown in Table 4.2,29-31 Of the 135 infants who received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine at 2, 4, and 6 months of age, a subset of 82 received a fourth dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine and a subset of 18 received a fifth dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine. A trend towards an increased frequency of redness and swelling was noted with successive doses.

TABLE 4 2,29-31ADVERSE EVENTS (%) OCCURRING WITHIN 72 HOURSFOLLOWING DOSES 1 TO 5 OF TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE IN CHILDREN WHO RECEIVED TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE FOR ALL DOSES

EVENT

PRIMARY

(N = 135 INFANTS)

BOOSTER

DOSE 1

2 Months

DOSE 2

4 Months

DOSE 3

6 Months

(N = 82 CHILDREN)

DOSE 4

15 to 20 Months

(N = 18 CHILDREN)

DOSE 5

4 to 6 Years

Local

Redness

Any

12.6

12.7

19.1

17.1

33.3

> 20 mm

2.2

0

3.8

NA†

22.2†

Swelling

Any

8.8

8.2

10.7

15.9

27.8

> 20 mm

0.7

0.7

3.1

NA†

16.7†

Pain*

8.1

3.7

2.3

7.3

11.1

Systemic

Fever > 101°F†

0.7

1.4

3.1

2.4

5.6

Anorexia

8.1

9.7

9.9

8.5

0

Vomiting

5.2

1.5

2.3

2.4

0

Drowsiness

28.9

17.9

4.6

6.1

5.6

Irritability**

8.1

7.4

7.6

3.7

0

* Moderate or severe = cried or protested to touch or when limb moved. ** Moderate or severe = prolonged or persistent crying that could not be comforted and refusal to play. † Rectal temperatures for primary series, oral temperatures for Dose 4 and Dose 5.Dose 5 reported as ≥100.1°F. † Post-dose 4, percent redness or swelling > 20 mm was not available; post-dose 4, 1.2% of subjects had redness > 50 mm, and 3.8% had swelling > 50 mm.30 Post-dose 5, 5.6% of children had redness > 50 mm, and none had swelling that exceeded 50 mm.31

A subset of children who participated in a German vaccine efficacy study were vaccinated with a fourth consecutive dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine in the study I92-2923-01 (Table 5). Data on the frequency of local and systemic reactions for 72 hours following vaccination was obtained from a diary provided to the parents at the time of vaccination and returned to the investigator by mail.

TABLE 52FREQUENCY OF ADVERSE EVENTS OCCURRING WITHIN THREE DAYS FOLLOWING VACCINATION WITH TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE IN CHILDREN 15 TO 18 MONTHS OF AGE WHO PREVIOUSLY RECEIVED THREE DOSES OF TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE

Event

Trial I92-2923-01*

4th dose

1, 010 subjects

Local Reaction

Any

481/1008 (47.7%)

Redness

Any Size

390/1007 (38.7%)

< 2.5 cm

257/1007 (25.5%)

> 2.5 cm

133/1002 (13.3%)

Swelling, any size

218/1004 (21.7%)

Pain

214/1002 (21.4%)

Systemic Reactions

Temperature > 100.4°F**

242/968 (25%)

Irritable

250/1005 (24.9%)

Loss of Appetite

146/1003 (14.6%)

Persistent Crying > 3 hours

8/1005 (0.8%)

* Subset of 12, 514 subjects who received three doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine in a German case control study of vaccine efficacy. ** Temperatures measured orally.

In an open label US study additional safety data are available in 15- to 20-month-old children who had previously received three doses of either Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine (n = 109) or whole-cell pertussis DTP vaccine (n = 30).32 Reaction rates are presented in Table 6.

TABLE 62,32ADVERSE EVENTS (%) OCCURRING WITHIN 72 HOURS FOLLOWING VACCINATION WITH TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE IN CHILDREN 15 TO 20 MONTHS OF AGE WHO HAD RECEIVED THREE PREVIOUS DOSES OF TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE OR THREE DOSES OF WHOLE-CELL PERTUSSIS DTP VACCINE

N*

ERYTHEMA

≥ 1 INCH

SWELLING

≥ 1 INCH

PAIN

TEMPERATURE

≥ 101°F**

IRRITABILITY

Tripedia Vaccine Primed

109

30.3

29.4

19.3

5.5

19.3

Whole-Cell pertussis DTP Vaccine Primed

30

23.3

20.0

10.3

3.3

13.3

* N = Number of Children **Temperatures measured rectally.

The frequency of adverse events following a fifth consecutive dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine administered to German children 4 to 6 years of age is shown in Table 7. This fifth dose study was an open label study that enrolled 580 subjects from 24 sites. These subjects were recruited from subjects who had participated in the case-control study of the efficacy of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine in which more than 12, 000 infants received three doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine. In the fifth dose study, information on systemic and local reactions was collected on diary forms for 3 days following vaccination for all subjects, and for 14 days following vaccination for a subset of 241 subjects. For 490 subjects, the actual sizes of local reactions > 5 cm, as measured by the parents, was also documented on the diary forms. Local reactions, including those measured as ≥11 cm, typically had an onset within the first three days after vaccination and generally resolved within five days. Three subjects had a local reaction that lasted more than 21 days one subject had swelling for 25 days, one subject had redness for 26 days, and one subject had redness for 28 days. Twenty-eight (4.8%) of 580 subjects had redness and/or swelling that led to a medical visit. There were no reported permanent sequelae associated with any local reactions. Thirty-two of 490 subjects (6.5%) had swelling reported as ≥11 cm, including 14 subjects (2.9%) who reported swelling of the entire upper arm. Swelling of the entire upper arm was not specifically solicited. Of 32 subjects with swelling reported as ≥11 cm, 19 also reported pain, 30 had redness and 2 had fever > 38°C. All cases of swelling ≥11 cm resolved spontaneously without treatment, except for a few subjects who were treated with cool packs. The subjects in the fifth dose study are not necessarily a subset of the 1, 010 German children for whom safety data following the fourth dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine are available (Table 5). However, children in both the fourth and fifth dose studies were recruited from subjects who had participated in the German case-control study. Available data from these studies suggest an increased frequency and severity of local reactions following the fifth successive dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine compared with the fourth dose.2 Additional safety data in 96 US children who received a fifth dose of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine following four previous doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine or Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine combined with ActHIB vaccine (TriHIBit vaccine) also demonstrated an increase in the frequency and severity of local reactions following the fifth dose compared with the first three doses.2

TABLE 72ADVERSE EVENTS (%) OCCURRING WITHIN 72 HOURS FOLLOWING A FIFTH DOSE OF TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE* IN GERMAN CHILDREN 4 TO 6 YEARS OF AGE WHO PREVIOUSLY RECEIVED FOUR DOSES OF TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE**

EVENT

PERCENT†

(N = 490-580)

Local

Redness (any)

59.8

> 5.0 cm

31.0

≥ 11.0 cm

6.1

Swelling (any)

61.4

> 5.0 cm

25.0

≥ 11.0 cm

6.5

Pain/Tenderness†

20.5

Systemic

Fever > 100.4°F¶

3.8

Loss of Appetite

7.3

Vomiting

2.2

Drowsiness

15.5

Fussiness§

5.9

* Note: one child was a protocol violation as he had received four doses of whole-cell DTP vaccinepreviously. ** These subjects are a subset of 12, 514 subjects who had received the first three doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine in the German case-control study of vaccine efficacy. † Redness ≥11 cm and swelling ≥11 cm available for 490 subjects and information on other reactions was available for 580 subjects. † Moderate or severe = crying or protesting to touch or crying when arm moved. ¶ Temperatures measured orally. § Moderate or severe = prolonged irritability, occasional crying and refusal to play or prolonged irritability, frequent crying, bed rest.

Table 8 lists the frequency of adverse events in 372 US children who received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine at 15 to 20 months of age and 240 US children who received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine at 4 to 6 years of age in a study conducted from 1989-1990. These children had previously received three or four doses of whole-cell pertussis DTP vaccine at approximately 2, 4, 6, and 18 months of age.2

TABLE 82ADVERSE EVENTS (%) OCCURRING WITHIN 72 HOURS FOLLOWING TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE IMMUNIZATIONS GIVEN AT 15 TO 20 MONTHS AND 4 TO 6 YEARS OF AGE IN CHILDREN WHO HAD RECEIVED THREE OR FOUR DOSES OF WHOLE-CELL PERTUSSIS DTP VACCINE

* Includes all occurrences of erythema. ** Includes all occurrences of swelling. NA Data not collected in this age group † Temperatures measured rectally for 15- to 20-month-old children and measured orally for 4 to 6 year-old children.

When Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine was used to reconstitute ActHIB vaccine (TriHIBit vaccine) and administered to children 15 to 20 months of age who had received 3 prior doses of whole-cell pertussis DTP vaccine, the systemic adverse experience profile was comparable to that observed when the two vaccines were given separately. An increase in rates of minor local reactions was observed within the 24-hour period after immunization when compared to the Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine and ActHIB vaccine administered separately. However, local adverse event rates of the combined vaccines were comparable when taking into consideration reactions observed at the ActHIB vaccine site.2 (Refer to ActHIB vaccine package insert.)

The results of an open label, non-controlled clinical study, of 2, 457 US children targeted to evaluate less common and more severe adverse events following three doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine in the primary series are shown in Table 9. Data were collected by parental interview at subsequent immunization visits, chart review and telephone calls to the parents 60 days after the third dose.

In the Swedish efficacy trial where 1, 419 recipients received the pertussis components in Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, three deaths due to invasive bacterial infections occurred. Further investigation revealed no evidence for a causal relation between vaccination and altered resistance to invasive disease caused by encapsulatedbacteria.33 While the hypothesis that the two variables are related cannot be ruled out in the Swedish trial, deaths due to invasive bacterial infections have been monitored in other trials. In contrast to the Swedish trial, in the German case-control study and US open-label safety study, 14, 971 infants received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine and no deaths due to invasive bacterial infections were reported.

In the German case-control study and US open-label safety study in which 14, 971 infants received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, 13 deaths in Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine recipients were reported. Causes of deaths included seven SIDS, and one of each of the following: enteritis, Leigh Syndrome, adrenogenital syndrome, cardiac arrest, motor vehicle accident, and accidental drowning. All of these events occurred more than two weeks past immunization.2 The rate of SIDS observed in the German case-control study was 0.4/1, 000 vaccinated infants. The rate of SIDS observed in the US open-label safety study was 0.8/1, 000 vaccinated infants and the reported rate of SIDS in the US from 1985-1991 was 1.5/1, 000 live births.34 By chance alone, some cases of SIDS can be expected to follow receipt of whole-cell pertussis DTP35 or DTaP vaccines.

Additional Adverse Reactions:

· As with other aluminum-containing vaccines, a nodule may be palpable at the injection sites for several weeks. Sterile abscess formation at the site of injection has been reported.3,36

· A few cases of peripheralmononeuropathy and of cranial mononeuropathy have been reported following tetanus toxoid administration, although available evidence is inadequate to accept or reject a causal relation.37

· A few cases of demyelinating diseases of the CNS have been reported following some tetanus toxoid-containing vaccines or tetanus and diphtheria toxoid-containing vaccines, although the IOM concluded that the evidence was inadequate to accept or reject a causal relationship.37

Adverse events reported during post-approval use of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine include idiopathic thrombocytopenic purpura, SIDS, anaphylactic reaction, cellulitis, autism, convulsion/grand mal convulsion, encephalopathy, hypotonia, neuropathy, somnolence and apnea. Events were included in this list because of the seriousness or frequency of reporting. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequencies or to establish a causal relationship to components of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine.2

Reporting of Adverse Events

The National Vaccine Injury Compensation Program, established by the National Childhood Vaccine Injury Act of 1986, requires physicians and other health-care providers who administer vaccines to maintain permanent vaccination records of the manufacturer and lot number of the vaccine administered in the vaccine recipients permanent medical record along with the date of administration of the vaccine and the name, address and title of the person administering the vaccine. The Act (or statute) further requires the health-care professional to report to the Secretary of the US Department of Health and Human Services the occurrence following immunization of any events set forth in the statute or the Vaccine Injury Table, including anaphylaxis or anaphylactic shock within 7 days; encephalopathy or encephalitis within 7 days, brachial neuritis within 28 days; or an acutecomplication or sequelae (including death) of an illness, disability, injury, or condition referred to above, or any events that would contraindicate further doses of vaccine, according to this Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine package insert.38,39

Reporting by parents or guardians of all adverse events after vaccine administration should be encouraged. Adverse events following immunization with vaccines should be reported by health-care providers to Vaccine Adverse Event Reporting System (VAERS). Reporting forms and information about reporting requirements or completion of the form can be obtained from VAERS through a toll-free number 1-800-822-7967.38,39